Reactivation of polyomavirus JCV in the brains of immunosuppressed individuals causes a devastating disease called progressive multifocal leukoencephalopathy (PML). There are no effective therapies available for PML. Although rare, the disease carries a >20% fatality rate and patients who survive are severely disabled due to brain damage caused by JCV infection and inflammation. Over a million individuals in the U.S. with acquired immune deficiency syndrome and individuals using immunosuppressive therapies are at risk for PML; depending on the underlying immunosuppressed condition, up to 3-5% will develop the disease. In particular, risk of PML limits the use of certain effective immunosuppressive drugs, e.g. natalizumab, adalimumab, etanercept, and infliximab for treatment of multiple sclerosis (MS), psoriasis, rheumatoid arthritis, and Crohn's disease, respectively. These drugs are counter-indicated for patients who are seropositive for JCV (up to 80% of healthy adults, and 30% of MS patients, as example). Previous strategies to develop a therapy for PML primarily focused on inhibiting JCV replication. Nucleoside analogues such as cytosine arabinoside, cidofovir and the anti-malarial drug mefloquine are effective in blocking JCV replication in culture, but they failed to demonstrate efficacy against PML in the clinic. The only treatment option for PML is to restore and allow the immune system to clear the viral infection; however, this often leads to immune-reconstitution inflammatory syndrome (IRIS) in which increased immune system activity actually increases the damage caused by the infection. The present project proposes to validate a novel mechanism of action, the activation of a host- encoded sirtuin protein by a single molecule that will simultaneously target different cellular sequelae of PML including JCV reactivation and IRIS. Sirtuins are NAD+-dependent deacetylases known for their role in regulating metabolic gene function and the inflammatory response. In addition, recent studies described herein point to a new role for Sirtuins as broad-spectrum viral restriction factors. A small molecule screen for sirtuin modulators identified broad-spectrum antivirals with nanomolar potency in inhibiting JCV growth in culture. The literature predicts the identified sirtuin modulators will also reduce inflammation, and importantl, one identified scaffold exhibited achievable biodistribution to the brain. Brain-penetrance minimizes the risk of poor drug availability to the viral and anti-inflammatory drug-targets of PML. The proposed SBIR phase 1 goal is to advance this hit to a lead while validating the hypothesis-driven antiviral and anti-inflammatory mechanisms of action. Confounding past attempts to develop an efficacious PML therapy, animal models do not exist for JCV that manifest the infection nor the symptoms of PML in the brain. The herein described mechanistic approach (as opposed to an antiviral-phenotypic approach) predicts pharmacodynamic markers to aid in determining a therapeutic window between tolerability and sufficient drug target-engagement. Such biomarkers will be measured in SBIR phase 2 and downstream to enable successful preclinical and clinical translation. In summary, a brain-penetrant lead that can simultaneously addresses viral infection and inflammatory components of PML, represents proof-of-principle for an innovative technology that addresses the devastating societal need for an effective PML therapeutic.